Intermediates for the preparation of 1, 3-dihydro-5-aryl-2h-1, 4-benzodiazepin-2-ones 4-oxides



Sept. 10, 1968 s, c. BELL 3,401,200

INTERMEDIATES FOR THE PREPARATION OF l,5-DIHYDRO-5ARYL2H-l, L-BENZODIAZEPIN--ONES 4OXIDES Filed June 9, 1967 United States Patent O 3,401,200 INTERMEDATES FOR THE PREPARATION F 1,3- DIHYDRG 5 ARYL 2H 1,4 BENZGDIAZEPIN- Z-ONES 4-0XIDES Stanley C. Bell, Penn Valley, Pa., assignor to American Home Products Corporation, New York, NX., a corporation of Delaware Continuation-impart of application Ser. No. 301,873, Aug. 13, 1963, which is a continuation-impart of applications Ser. No. 283,966 and Ser. No. 283,967, May 29, 1963. This application June 9, 1967, Ser. No. 644,900

6 Claims. (Cl. 260-562) ABSTRACT 0F THE DSCLOSURE 2-(Z-hydroxyaminoacetamido)carboxylic acyl ketones, valuable intermediates for the preparation of 1,3-dihydro- 2H-1,4-benzodiazepin-2-ones having a psycholeptic effect in mammals, are prepared from 2(2-haloacetamido) carboxylic acyl ketones by treatment with hydroxylamine.

This application is a continuation-impart of my copending application Ser. No. 301,873 filed Aug. 13, 1963, now abandoned, which in turn was a continuation-inpart of application Ser. No. 283,966 and Ser. No. 283,967, both filed May 29, 1963, and now abandoned.

This invention relates to novel compositions of matter classified in the art of chemistry as 2-(2-hydroxyaminoacetamido)acylbenzene's, valuable intermediates for the preparation of benzodiazepin-Z-ones.

The invention sought to be patented in its principal composition aspect, is described as residing in the concept of a chemical compound having a molecular structure in which there is attached, to the benzene nucleus, a benzoyl radical at one position and, at a position ortho thereto, a 2hydroxyaminoacetamido radical.

The tangible embodiments of the composition aspect of the invention possess the inherent general physical properties lof being crystalline solids. Examination of compounds produced according to the hereinafter described process reveals upon nuclear magnetic resonance, ultraviolet and infrared spectrographic analyses, spectral data confirming the molecular structure hereinbefore set forth. F or example, the

frequency characteristic of the compounds is evident. The aforementioned physical characteristics, taken together with the nature of the starting materials, the mode of synthesis and reactions of the compositions sought to be patented positively confirm their structure.

The tangible embodiments of the compositions of the present invention possess the inherent applied use characteristic of being useful as intermediates for the preparation of known aryl 1,3 dihydro 2H 1,4 benzodiazepin-Z-one 4-oxides, as, for example, in South African Patents Nos. 60/4930 to 60/4936, inclusive, and 60/ 4938, and U.S. Patents Nos. 3,100,770 and 3,117,965, which in -turn possess the inherent applied use characteristics of exerting a psycholeptic effect in mammals, as evidenced by evaluation according to standard test procedures.

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The invention sought to be patented in a principal process of making aspect is described as residing in the concept of converting the 2haloacetamido radical, which is attached in the 2-position of the benzene nucleus, of a 2-(2haloacetamido)acylbenzene to the 2-hydroxyaminoacetamido radical by treatment with hydroxylamine.

The term nucleus is used herein as defined and used in Hackhs Chemical Dictionary, McGraw-Hill Book Company, Inc., 1944, at p. 586, and as specifically applied to benzene nucleus at pp. 107-110. The term benzene nucleus as above defined and as used herein and by those skilled in the art means the benzene ring of carbon atoms, wherein all valences are satisfied by hydrogen or other monovalent substituents.

The term radical is used herein as defined and used in Hackhs Chemical Dictionary, McGraw-Hill Book Company, Inc., 1944, at pp. 714 and 715. It is a specific group of named atoms in a certain relationship and contains only one free valence bond which must be satisfied, here by attachment to the 'benzene nucleus.

The manner and process of making and using the compositions and processes of the invention will now be generally described so as to enable a person skilled in the art of chemistry to use the same, as follows:

The new processes of my invention are illustrated schematically for a specific embodiment in FIGURE l, and more specifically in FIGURE 2 of the attached drawing, to which the numerals in the following description refer.

When a 2-(2-haloacetamido)benzophenone 1, 4 is treated with hydroxylamine or a salt thereof under the hereinafter described conditions, I have discovered that, contrary to what would be expected by one with ordinary skill in the art of chemistry, even in the presence of a large excess of hydroxylamine, a substantially selective displacement of halogen occurs and surprisingly, a good yield of 2-(2-hydroxyaminoacylamino) phenyl aryl ketone 2, 5 is obtained instead of the classical ketone-hydroxylamine reaction derivative, i.e., the corresponding oxime. This reaction is preferably performed ata pH range of from about 4 to about 9 in a solvent mixture comprising water and a water-soluble organic solvent such as methanol, ethanol, dioxane, or dimethylformamide, in order to obtain optimum yield. The reaction may also be run in non-aqueous media, with or Without a watersoluble organic solvent. Preferably the reaction is conducted at temperatures ranging from about 30 C. to the reflux temperature of the solvent mixture for a period of time ranging from about one-quarter to about two hours. The reaction mixture can then be diluted with water to precipitate the 2-(2-hydroxyaminoacetamido)phenyl aryl ketone 2, 5 in a readily isolatable form. The intermediate 2-(2-hydroxyaminoacetamido)phenyl aryl ketone 2, 5 need not be isolated or, if isolated, said intermediate may be redissolved in a wettable aqueous or non-aqueous organic solvent. On treatment with a cyclizing agent there is obtained a 1,3dihydro5-aryl-2H-1,4-benzodiazepin-2 one 4-oxide 3, or when the cyclizing agent is an alkali metal hydroxide, its alkali metal salt. When the salt is obtained, neutralization with acid gives the 1,3-dihydro- 5aryl2H1,4-benzodiazepin-2-one 4oxide 3.

The cyclizing medium may be one containing an ionizable acid such as acetic, sulfuric, benzenesulfonic, paratoluenesulfonic, or hydrochloric acid, or one containing an alkali metal or alkaline earth metal hydroxide such as sodium, potassium, or calcium hydroxide.

The 2(2-haloacetamido)phenyl aryl ketones employed as starting materials in conducting our process are known or are readily prepared by procedures known to those skilled in the art.

It will be apparent from the disclosure herein to those skilled in the art of organic chemistry that for the purposes of this invention certain of the carbon and nitrogen atoms of the 2-(2-haloacetamido) phenyl mono-cyclic aryl ketones employed as starting materials can be substituted with groups which do not interfere with the hydroxyamination reaction involving the 2-halo atom. Thercfore, in the processes of the invention, exception for any limitations expressed in this specification all 2-(2-haloacetamido)phenyl mono-cyclic aryl ketones can be employed .as starting materials in the process of making aspect of this invention. Similarly, in 2-(2-haloacylamino) phenyl mono-cyclic aryl ketones and in the 2-(2-hydroxyaminoacylamino)phenyl mono-cyclic aryl ketones formed as intermediates the acylamino nitrogen can be substituted (FIGURE 2, Z) with hydrogen, an alkyl group such as methyl, ethyl, isopropyl, an alkenyl group such as allyl and methallyl or a lower aralkyl group such as benzyl or phenethyl. The 2-carbon of the acetamido group, i.e., that to which the carbonyl group is attached, in the 2-hal0- acetamido compounds and in the 2-hydroxyamino-acetamido compounds can be substituted (FIGURE 2, X and Y) with hydrogen or with alkyl; and the aromatic-aliphatic radicals benzyl, or phenethyl, wherein the phenyl group may be similarly substituted or unsubstituted.

The benzene nucleus bearing the hydroxyaminocetamido radical and carboxylic acyl radical can have one or more monovalent substituents other than hydrogen, as for example, but without limitation, lower alkyl, alkoxy, al-

kylthio, nitro, amino, hydroxy, halogen preferably chlorine, lbromine, triiluoromethyl or alkylsulfonyl at the 3, 4, 5- or 6positions. Such substituents do not interfere with the course of the reactions here involved. The carboxylic acyl group can 'be aroyl, such as benzoyl, 2- or 3- thenoyl; 2- or 3furoyl; 2, 3- or 4pyridylcarbonyl; or 1- or 2-naphthoyl or it can be alkanoyl. The aryl nucleus of the aryl-keto group can bear one or more simple substituents inert to the reactions herein described, such as lower alkyl, alkoxy, alkylthio, nitro, amino, hydroxy, halogen, preferably chlorine, bromine, trifluoromethyl, or alkylsulfonyl and such substituted aryl-keto compounds are full equivalents of the unsubstituted aryl nucleus for the purposes of the present invention.

From the disclosure herein illustrating the invention as applied to starting materials which produce compounds wherein the 5position substituent is phenyl or substituted phenyl, it will be apparent to organic chemists that other mono-cyclic nuclei can be in the starting materials in lieu of phenyl without affecting the course of the reactions involved in the hydroxyamination and the subsequent ring closure. Accordingly, such reactions wherein the phenyl group is replaced by 2- or 3thienyl; 2- or 3-furyl; and 2, 3- or 4pyridyl radicalsk are the full equivalents of the invention as particularly claimed.

When the starting compounds are substituted as herein-before recited, it will be apparent herefrom to those skilled in the art of chemistry that the intermediate compounds and the nal products formed by the process of invention will bear, correspondingly, the same substituents.

It also will be apparent herefrom to one skilled in the art of organic chemistry that the hereinbefore described starting compounds, namely, the 2-(2-haloacetamido) phenyl monocyclic aryl ketones can be either 2-(2-chloroacetamido)phenyl aryl ketones, 2(2-bromoacetamido) phenyl aryl ketones or 2-(2-iodoacetamido)phenyl aryl ketones, namely, those subject to nucleophlic displacement or the equivalent thereof such as 2-(2-tosyloxyacetamido)phenyl mono-cyclic aryl ketones. For best results when using the chloroand bromocompounds, it is preferred to add a small amount of a water-soluble iodide salt such as sodium or potassium iodide.

The following example illustrates the .best mode contemplated by the inventor of using the claimed process of the invention and of the manner of making and using a speciiic embodiment of the claimed compositions of the invention.

Example l To a mixture of 2.1 g. of hydroxylamine hydrochloride and 5 ml. of 4 N sodium hydroxide in 75 ml. of alcohol and 25 ml. of water add 3.6 g. of 5-chloro-2-(2-iodoacetamido)benzophenone and reux the reaction mixture for 20 minutes. Add sodium hydroxide to the resultant solution to neutralize any unreactcd hydrochloride. Dilute the solution with ml. of water. Filter from impurities, acidity the solution vwith acetic acid and collect the rcsultant solid. Recrystallize from ethol to obtain 7-chloro- 1,3-dihydro-S-phenyl-ZH-1,4-benzodiazepin-2-one 4oxide, M.P. 23S-237 C.

The following examples further illustrate the claimed processes and the method for preparing and using the compositions of the invention.

Prepare 7-chloro-1,3-dihydro-5-(2-thienyl)2H1,4ben zodiazepin-Z-one 4oxide from 2-(2-iodoacetamido)5 chlorophenyl 2-thienyl ketone by the procedure described above.

Prepare l,3-dihydro-S-phenyl-7-triuoromethyl-ZH-1,4- benzodiaZepin-2one 4oxide from 2-(2-bromoacetamido)- S-triiiuoromethylbenzopbenone by the procedure described above.

Prepare 7,8-dichloro-1,3-dihydro5-phenyl-2H1,4-benzodiazepin-Z-one 4oxide from 2-(2-bromoacetamido)4,5 dichloro-benzophenone by the procedure described above.

Prepare 1,3-dihydro-7-nitro-5-phenyl-1,4 benzodiazepin-2-one 4oxide from 2-(2-iodoacetamido)5nitroben zophenone by the procedure described above.

Prepare 1,3dihydro-7-methylsulfonyl-S-phenyl-ZH-1,4- benzodiazepin-2-one 4oxide from 2-(2-iodoacetamido)5 methylsulfonylbenzophenone by the procedure described above.

Prepare 1,3-dihydro-5-(o-chlorophenyl)-2H-1,4benzo diazepin-Z-one 4oxide from o(2-iodoacetamido)phenyl o-chlorophenyl ketone by the procedure described above.

Prepare 1,3-dihydro-5-(p-methoxyphenyl)-2H-1,4ben zodiazepin-Z-one 4oxide from o-(2-iodoacetamido)phenyl p-methoxyphenyl ketone by the procedure described above.

Prepare l,3-dihydro-5-(p-tolyl)2H1,4benzodiazepin 2one 4oxide from o-(2iodoacetamido)phenyl p-tolyl ketone by the procedure described above.

Prepare 1,3 dihydro 5 (m-triuoromethylphenyl) 2H 1,4 benzodiazepin-Z-one 4oxide from o-(2-iodoacetamido)phenyl m-triiiuoromethyl phenyl ketone by the procedure described above.

Prepare 7 chloro 1,3-dihydro-3-methyl-S-phenyl- 2H-1,4-benzodiazepin-2-one 4oxide from 5-chloro-2-(2- iodopropionamido)benzophenone by the procedure described above.

Prepare 7 bromo 5 (p chlorophenyl)-l,3dihydro 2H-l,4-benzodiazepin2-one 4oxide, M.P. 260-26l dec., lfrom 5 bromo-2(2-bromoacetarnido)phenyl p chlorophenyl ketone by the procedure described above.

`Prepare 7 chloro 1,3 dihydro-l-methyl-S-phenyl- 2H-l,4benzodiazepin 2 one 4oxide, M.P. 178-180, from 5 chloro 2 (2 iodo-N-methylacetamido)benzophenone by the procedure described above.

Example 2 Stir a mixture ofk 5.0 g. of 5-chloro-2-(2-iodoacetami do)benzophenone, 7.0 g. of hydroxylamine hydrochloride, 20 ml. of water, 2O ml. of 4 N sodium hydroxide solution, and 60 ml. of dimethylformamide at room temperature until a clear solution results (one-half hour).

Add 100 ml. of water and collect the resultant solid and recrystallize from benzene to obtain pure 5-chloro-2-(2- hydroxyaminoacetamido)'benzophenone, M.P. 129-13l.

AnaIysz's.-Calcd. for C15H13C1N2O3: C, 59.10; H, 4.30, Cl, 11.64; N, 9.21. Found: C, 59.38; H, 4.16; Cl, 11.70; N, 9.00.

Prepare 2,5 dichloro 2 (2 hydroxyaminoacetamido)benzophenone from 2',5 dichloro-2-(2-iodoacetamido) phenzophenone by the procedure described above.

Prepare o-(2-hydroxyaminoacetamido) phenyl 2-thienyl ketone from o-(2-iodoacetamido)phenyl 2-thienyl ketone by the procedure described above.

Prepare 5 triuoromethyl-Z-(2-hydroxyaminoacetamdo)benzophenone from 2 (2 'bromoacetamido)5-tri uoromethylbenzophenone by the procedure described above.

Prepare 2-(2-hydroxyaminoacetamido) 5,6 dichlorobenzophenone from 2-(2-bromoacetamido)-5,6-dichloro benzophenone by the procedure described above.

Prepare 2 (2 hydroxyaminoacetamido)-S-nitrobenzophenone from 2-(2-iodoacetamido) 5 nitro'benzophenone by the procedure described above.

Prepare 2 (2 hydroxyaminoacetamido)-S-methylsulfonylbenzophenone lfrom 2 (2 iodoacetamido)-5- methylsulfonylbenzophenone by the procedure described above.

Prepare o-(Z-hydroxyaminoacetamido) phenyl o-chlorophenyl ketone from o-(2-iodoacetamido) phenyl o-chlorophenyl ketone by the procedure described above.

Prepare o (2 hydroxyaminoacetamido) phenyl p-methoxyphenyl ketone from o-(2-iodoacetamido)pheny] p-methoxyphenyl ketone by the procedure described above.

Prepare o (2 hydroxyaminoacetamido)phenyl m-triuoromethyl phenyl ketone from o-(2-iodoacetamido) phenyl m-trilluoromethyl phenyl ketone by the procedure described above.

Prepare o-(2-hydroxyaminoacetamido)phenyl p-tolyl ketone from o-(2-iodoacetamido) phenyl p-tolyl ketone by the procedure described above.

Prepare 5 chloro-2-(2hydroxyaminopropionamido) benzophenone from 5chloro-2-(2-iodopropionamido) benzophenone by the procedure described above.

Example 3 Stir a mixture of 4.0 g. of 5-chloro-2-(2-chloroacetamido)benzophenone, 7.0 g. of hydroxylamine hydrochloride, ml. of water, 20 ml. of 4 N sodium hydroxide, 100 ml. of dimethylformamide and 0.2 g. of sodium iodide at 50 until a clear solution is obtained (ca. onehalf hour). Add 100 ml. of water. Cool to precipitate and rccrystallize the precipitate in alcohol and then benzene to obtain 5-chloro-2-(2-hydroxyaminoacetamido) benzophenone, M.P. 129-131".

Example 4 Acidify the clear solution of Example 3 with hydrochloric acid and warm to obtain 7-chloro-l,3-dhydro5 phenyl-2H-1,4-benzodiazepin-2-one 4oxide, M.P. 235- 237 as a precipitate.

Example 5 Add a suspension of 1.0 g. of 5-chloro-2-(2-hydroxyaminoacetamido)benzophenone in ml. of 50% alcohol, 2 ml. of 6 N hydrochloric acid and heat the mixture on the steam bath for l0 minutes. Dilute solution with an equal volume of water and cool to obtain a precipitate of 7 chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin- 2-one 4-0xide.

Example 6 Warm a solution of S-chloro (2 hydroxyaminoacetamido)benzophenone in acetic acid containing gaseous hydrochloric acid on a steam bath and then dilute with water to obtain 7-chloro 1,3 dihydro-S-phenyl-ZH-1,4- benzodiazepin-2-one 4-oxide.

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Example 7 Add to a mitxure of 2.1 g. of hydroxylamine hydro chloride and 5 ml. of 4 N sodium hydroxide in 75 ml. of alcohol and 25 ml. of water, 3.6 g. of 5-chloro-2-(2- iodoacetamido)benzophenone (or the corresponding 2- chloroacetamido compound in the presence of 0.2 g. of sodium iodide) and reux the mixture for 20 minutes. Add sodium hydroxide to the resultant solution and dilute the solution with ml. of Water. Filter the solution and acidify with acetic acid. Collect resultant solid and recrystallize from ethanol to obtain 7-chloro-l,3dihydro-5 phenyl-ZH-l,4-benzodiazepin-2-one 4oxide, M.P. 235- 237 C.

Prepare 7 chloro 1,3 dihydro-5-(2-thienyl)-2H-1,4- benzodiazepin-Z-one 4-oxide from 2-(2-hydroxyarninoacetamido)-5-chlorophenyl 2-thienyl ketone by the procedure described above.

Prepare 1,3-dihydro-5-phenyl-7-triuoromethyl-ZH-1,4- benzodiazepin-Z-one 4-oxide from 5-trifluoromethyl-2-(2- hydroxyaminoacetamido)benzophenone by the procedure described above.

Prepare 7,8 dichloro 1,3 dihydro-5-phenyl-2H-1,4 benzodiazepin-Z-one 4-oxide from 2-(2-hydroxyarnino acetamido)-4,5-dichlorobenz0phenone by the procedure described above.

Prepare 1,3 dihydro 7-nitro-5-phenyl-2H-1,4-benzodiazepin-Z-one 4-oxide from 2-(2-hydroxyaminoacetamido)5-nitr0benzophenone `by the procedure described above.

Prepare 1,3 dihydro 7 methylsulfonyl-S-phenyl-ZH- 1,4-benzodiazepin-2-one 4-oxide from 2-(2-hydroxyaminoacetamido)-5-methylsulfonylbenzophenone by the procedure described above.

Prepare 1,3-dihydro-S-(o-chlorophcnyl)-2H-1,4-benzo diazepin-Z-one 4-oxide from o-(Z-hydroxyaminoacetamido)phenyl o-chlorophenyl ketone lby the p-rocedure described above.

Prepare 1,3 dihydro 5 (p-methoxyphenyl)-2H-1,4- benzodiazepin-Z-one 4-oxide from o-(2-hydroxyaminoacetamido) phenyl p-methoxyphenyl ketone by the procedure described above.

Prepare 7 chloro -1,3-dihydro-5-(o-chlorophenyl-ZH- 1,4-benzodiazepin-2-one 4-oxide from o-(2-hydroxyaminoacetamido) phenyl o-chlorophenyl ketone by the procedure described above.

Prepare 1,3 dihydro-S-(p-tolyl)-2H-1,4-benzodiazepin 2-one 4-0xide from o-(2-hydroxyaminoacetamido)phenyl p-tolyl ketone by the procedure described above.

Prepare 1,3 dihydro-5-(m-triuoromethylphenyl)-2H- 1,4-benzodiazepin-2-one 4-oxide from o-(2-hydroxyaminoacetamido)phenyl m-triuoromethylphenyl ketone by the procedure described above.

Prepare 7 chloro 1,3-dihydro-3-methyl-5-phenyl-2H- 1,4-benzodiazepin-2-one 4-oxide from 5-chloro-2-(2-hydroxyaminopropionamido)benzophenone by the procedure described above.

Example 8 amido) phenyl] phenyl ketone comprising: converting the Z-haloacetamido radical which is attached in the 2-position of the phenyl nucleus, of a 2[(2-haloacetamido) phenyl] phenyl ketone to the Z-hydroxyaminoacetamdo radical by treatment of the benzophenone compound with hydroxylamine.

5. The process of claim 4, wherein the acetamidophenyl of the 2[ (2haloacetarnido)phenyl] phenyl ketone is substituted with chlorine at the 5position.

6. The process of claim 5, wherein the phenyl group of the 2[.(haloacetamido) phenyl] phenyl ketone is o-chlorophenyl.

References Cited Noller Chemistry of Organic Compounds, 2nd ed., pp. 210-11, Philadelphia, Saunders, 1957.

HENRY R. JILES, Primary Examiner.

NATALIE TROUSOF, Asssfant Examiner. 

